The longrange goal of the research proposed in this application is to elucidate the nature of the metabolic imbalances and biochemical changes responsible for the late complications of diabetes. Epidemiological and experimental investigations both are consistent with the hypothesis that the development of late diabetic complications is largely the consequence of metabolic imbalances and dysfunction which greatly increase the susceptibility of vessels and nerves to injury by risk factors independent of the diabetic milieu. Such risk factors include hypertension, cigarette smoking, atherogenic lipoproteins, and hypoxic/ischemic injury. Several lines of evidence indicate that the diabetic milieu induces a hypoxia-like state "diabetic pseudohypoxia" despite the presence of normal tissue oxygen levels. This hypoxia-like condition (an increased ratio of NADH/NAD+) appears to be largely the consequence of increased oxidation of sorbitol to fructose and increased oxidation of fatty acids. A cascade of metabolic imbalances and oxidative stress induced by this hypoxia-like state appears to play an important role in mediating early vascular and neural changes induced by diabetes and by acute hyperglycemia in nondiabetic rats. The experiments outlined in this proposal are designed to elucidate the role of these metabolic imbalances and oxidative stress associated with diabetic pseudohypoxia in mediating vascular and neural dysfunction. To this end diabetes will be induced in rats and vascular leakage and blood flow will be assessed in untreated rats and in rats treated with pharmacological agents known to impact (beneficially) on metabolic imbalances and dysfunction induced by hypoxia and ischemia to the heart and brain. Agents which impact more specifically on diabetes-induced vascular and neural changes also will be investigated. These agents include free radical scavengers, dichloroacetate, carnitines, C-peptide, and inhibitors of sorbitol dehydrogenase. In parallel experiments the effects of these agents will be examined on metabolism of tissues prone to development of diabetic complications including retina, peripheral nerve, and aorta. The potential significance of this research is that it may provide new insights regarding the pathogenesis of late complications of diabetes and may contribute to the development of new therapeutic approaches for the prevention and treatment of diabetic complications.